CN106236714A - A kind of oseltamivir phosphate tablet and preparation method thereof - Google Patents
A kind of oseltamivir phosphate tablet and preparation method thereof Download PDFInfo
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- CN106236714A CN106236714A CN201610364358.1A CN201610364358A CN106236714A CN 106236714 A CN106236714 A CN 106236714A CN 201610364358 A CN201610364358 A CN 201610364358A CN 106236714 A CN106236714 A CN 106236714A
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- tablet
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- oseltamivir phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
Abstract
The present invention provides a kind of oseltamivir phosphate tablet and preparation method thereof.Oseltamivir phosphate tablet of the present invention comprises sucralose, aspartame or its mixture as sweeting agent, containing other pharmaceutically acceptable adjuvants, described oseltamivir phosphate tablet has good mouthfeel, good stability and the advantage such as portable to take simultaneously.On the other hand present invention also offers the preparation method preparing described oseltamivir phosphate tablet, the method is easy, cheap, is suitable for industrialized production.
Description
Technical field
The present invention relates to field of medicine preparations, more particularly, to a kind of oseltamivir phosphate tablet and preparation method thereof.
Background technology
Oseltamivir phosphate, chemistry entitled (-)-(3R, 4R, 5S)-4-acetamide-5-amino-3-(1-ethylpropoxy) cyclohexene-1-carboxylic acid, ethyl ester
Phosphate.Chemical structural formula is as follows:
Oseltamivir phosphate has the activity of the strongest suppression neuraminidase, and all effective to A, Type B influenza virus, its character and preparation method etc. is believed
Breath is disclosed in WO 1998007685 A1 and WO 1996026933 A1.
The dosage form that oseltamivir phosphate lists at present has granule, capsule and dry suspension etc..Granule or dry suspension are suitable for joining before use
Make liquid preparation, it is simple to old man, child and be not suitable for the crowd of swallowing and take, but oseltamivir phosphate be a kind of king-sized medicine of bitterness,
Therefore its pharmaceutical composition is difficult to swallow.Generally by adding sweeting agent in the composition or using capsule preparations form to cover oseltamivir phosphate
Bitterness.
Chinese patent CN 101389323 B discloses a kind of pharmaceutical composition, and it contains excipient and oseltamivir phosphate, wherein this excipient
Selected from 25 DEG C, 70% time equilibrium moisture content of relative humidity be more than one of the sugar of below 1 weight % and sugar alcohol, and institute in this sugar and sugar alcohol
The glucose contained and the content of mannose are respectively below 0.01 weight %.In order to suppress the bitterness of this pharmaceutical composition, described invention is additionally added
Substantial amounts of sweeting agent (such as sucrose or steviosin) is to cover bitterness.
Chinese patent CN 1820774 B discloses a kind of oseltamivir phosphate granula and preparation method thereof, and described granule comprises 1.97～19.8 weights
The oseltamivir phosphate of amount %, the diluent of 75.0～97.5 weight %, the binding agent of 0.1～5.0 weight %, and the edible perfume (or spice) of 1.0～5.0 weight %
Essence, sweeting agent and/or food coloring.
Tablet currently without oseltamivir phosphate lists, and lacks the research of the tablet to oseltamivir phosphate in prior art.
Summary of the invention
Summary of the invention
In prior art described above, disclosed embodiment employs the sweeting agents such as sucrose, steviosin and saccharin sodium, however sweet disclosed in these
After taste agent and oseltamivir phosphate are applied in combination, although it can cover the bitterness of oseltamivir phosphate, but it can affect phosphoric acid Ao Sita in prescription
The stability of Wei, causes impurity rapid development in oseltamivir phosphate compositions, is unfavorable for that the long-term of medicine preserves and safe handling.
Meanwhile, oseltamivir phosphate tablet has easy to carry, good stability, be easy to preserve and the advantage such as easy to use, is that a kind of Worth Expecting is opened
The dosage form sent out, is particularly suitable for child or the oral cavity disintegration tablet of old people garment, chewable tablet or buccal tablet.Described tablet can effectively strengthen child and old man
The compliance of medication, solve in particular cases (as under water deficit conditions, the patient of dysphagia) an administration difficult problem.But due to described sheet
Agent is all to disperse in oral cavity or dissolve, and oseltamivir phosphate bitterness is the heaviest, therefore compared to other dosage forms, described dosage form is carried out taste masking and especially must
Indispensable.Therefore, find that a kind of can be good at carrying out oseltamivir phosphate tablet taste masking to have the sweeting agent of good stability be must not simultaneously
Can lack.But the oseltamivir phosphate tablet stable, taste is good is not disclosed in current prior art.
The present inventor has carried out sufficient research to oseltamivir phosphate, gropes through many experiments, very unexpectedly, it was discovered that using sucralose
Or aspartame as sweeting agent time, can effectively correct the taste of oseltamivir phosphate tablet, there is excellent stability simultaneously.
Here, one aspect of the present invention provides a kind of oseltamivir phosphate tablet；Especially, it is provided that a kind of oseltamivir phosphate oral cavity disintegration tablet, chewable tablet or
Buccal tablet.
On the other hand a kind of preparation method preparing described oseltamivir phosphate tablet is provided.
Term defines
In the present invention " % ", unless otherwise indicated refer both to mass percent.
In the present invention " RRT ", unless otherwise indicated refer to the relative retention time in chromatography detection.
In the present invention " v/v ", unless otherwise indicated refer to volume ratio.
Concrete numerical value involved in the present invention refers to this numerical value ± 5%.
Detailed Description Of The Invention
The present invention provides a kind of Oseltamivir tablet, and described tablet comprises oseltamivir phosphate, sweeting agent and other pharmaceutically acceptable adjuvants, wherein
Described sweeting agent is sucralose or aspartame.
The present invention also provides for a kind of oseltamivir phosphate tablet, and described tablet comprises oseltamivir phosphate, sweeting agent and other pharmaceutically acceptable adjuvants,
Wherein said sweeting agent is sucralose, aspartame or its mixture.
Wherein said oseltamivir phosphate content is 5mg, 10mg, 30mg, 45mg or 75mg, based on Oseltamivir.
The content of wherein said sweeting agent is 0.1%～5.0%.
Wherein said pharmaceutically acceptable adjuvant can be filler, binding agent, disintegrating agent, fluidizer, lubricant, pH adjusting agent and eat
One or more in essence.
Wherein said filler can be but not limited to lactose, microcrystalline Cellulose, mannitol, sorbitol, maltose alcohol, xylitol, Semen Maydis shallow lake
One or more in powder, dextrin, maltodextrin, pregelatinized Starch, sucrose and gelatin.
Wherein said binding agent can be but not limited to methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvidone, crystallite fibre
One or more in dimension element and low-substituted hydroxypropyl cellulose；Preferably hydroxypropyl cellulose or polyvidone.
Wherein said disintegrating agent (including the first disintegrating agent or the second disintegrating agent) can be but not limited to cross-linking sodium carboxymethyl cellulose, crosslinking
One or more in polyvidone, carboxymethyl starch sodium, corn starch, low-substituted hydroxypropyl cellulose；Preferably cross-linking sodium carboxymethyl cellulose or friendship
Connection polyvidone.
Wherein said fluidizer can be but not limited to silica sol or Pulvis Talci or its mixture.
Wherein said lubricant can be but not limited to sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, sucrose stearate,
One or more in hydrogenated vegetable oil, stearic acid, silica sol, Pulvis Talci and polyethylene glycol 6000；Preferably sodium stearyl fumarate.
Wherein said pH adjusting agent/acidic flavoring agent, can be but not limited to citric acid and the mixture of hydrate salt pharmaceutically acceptable with it, lemon
Lemon acid dihydride alkali metal salt, sodium lactate, sodium succinate, preferably monohydrate potassium.
Wherein said edible essence can be but not limited to peach flavor, orange flavor, strawberry essence, cream flavour, apple essence, Fructus Ananadis comosi
One or more in essence and flavoring banana essence；Preferably peach flavor or orange flavor.
In certain embodiments, described oseltamivir phosphate tablet is oral cavity disintegration tablet, chewable tablet or buccal tablet.
In certain embodiments, described oseltamivir phosphate tablet is chewable tablet or buccal tablet, and the sheet heart of wherein said chewable tablet or buccal tablet is adopted
The sheet heart is made to have a hole running through two sides by special punch die or other modes.The described heart it can be avoided that tablet is gulped down and is caused suffocating of child by mistake,
Improve the safety of children.
In certain embodiments, oseltamivir phosphate oral cavity disintegration tablet of the present invention, comprise 2.0%～50.0% or 2.5～40.0% or 15.0%～40.0%
Oseltamivir phosphate, the sweeting agent of 0.1%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is sucralose or A Si
Ba Tian.
In certain embodiments, oseltamivir phosphate oral cavity disintegration tablet of the present invention, comprise 2.0%～50.0% or 2.5～40.0% or 15.0%～40.0%
Oseltamivir phosphate, the sweeting agent of 0.1%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is sucralose, A Si
Ba Tian or its mixture.
In certain embodiments, oseltamivir phosphate chewable tablet of the present invention, comprise 1.0%～50.0% or 2.5～40.0% or 5.0%～20.0%
Oseltamivir phosphate, the sweeting agent of 0.1%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is sucralose or A Si
Ba Tian.
In certain embodiments, oseltamivir phosphate chewable tablet of the present invention, comprise 1.0%～50.0% or 2.5～40.0% or 5.0%～20.0%
Oseltamivir phosphate, the sweeting agent of 0.1%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is sucralose, A Si
Ba Tian or its mixture.
In certain embodiments, oseltamivir phosphate buccal tablet of the present invention, comprise 2.0%～the department of phosphoric acid Austria of 50.0% or 8.0%～40.0%
His Wei, the sweeting agent of 0.5%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent is sucralose or aspartame.
In certain embodiments, oseltamivir phosphate buccal tablet of the present invention, comprise 2.0%～the department of phosphoric acid Austria of 50.0% or 8.0%～40.0%
His Wei, the sweeting agent of 0.5%～5.0% and other pharmaceutically acceptable adjuvants, wherein said sweeting agent be sucralose, aspartame or its mix
Compound.
In certain embodiments, oseltamivir phosphate oral cavity disintegration tablet of the present invention, chewable tablet or buccal tablet comprise the edible essence of 0.05%～0.3%.
In certain embodiments, oseltamivir phosphate oral cavity disintegration tablet of the present invention, comprise the oseltamivir phosphate of 2.5%～40.0%, 45.0～90.0%
Filler, the disintegrating agent of 4.0%～10.0%, the binding agent of 0.5%～3.0%, the sweeting agent of 0.2%～2.0%, the lubricant of 0.5%～1.0%,
The fluidizer of 0.2%～1.0%, and the edible essence of 0.05%～0.3%, wherein said disintegrating agent comprises the first disintegrating agent and the second disintegrating agent,
Wherein said sweeting agent is sucralose or aspartame.
In certain embodiments, oseltamivir phosphate oral cavity disintegration tablet of the present invention, comprise the oseltamivir phosphate of 2.5%～40.0%, 45.0～90.0%
Filler, the disintegrating agent of 4.0%～10.0%, the binding agent of 0.5%～3.0%, the sweeting agent of 0.2%～2.0%, the lubricant of 0.5%～1.0%,
The fluidizer of 0.2%～1.0%, and the edible essence of 0.05%～0.3%, wherein said disintegrating agent comprises the first disintegrating agent and the second disintegrating agent,
Wherein said sweeting agent is sucralose, aspartame or its mixture.
In certain embodiments, oseltamivir phosphate chewable tablet of the present invention, comprise the oseltamivir phosphate of 1.3%～40.0%, 48.0～94.0%
Filler, the disintegrating agent of 1.0%～5.0%, the binding agent of 1.0%～3.0%, the sweeting agent of 0.2%～2.0%, the lubricant of 0.5%～1.0%,
The fluidizer of 0.2%～0.5%, the pH adjusting agent of 0.25%～2.0% and 0.1%～the edible essence of 0.30%, wherein said sweeting agent is sucralose
Or aspartame.
In certain embodiments, oseltamivir phosphate chewable tablet of the present invention, comprise the oseltamivir phosphate of 1.3%～40.0%, 48.0～94.0%
Filler, the disintegrating agent of 1.0%～5.0%, the binding agent of 1.0%～3.0%, the sweeting agent of 0.2%～2.0%, the lubricant of 0.5%～1.0%,
The fluidizer of 0.2%～0.5%, the pH adjusting agent of 0.25%～2.0% and 0.1%～the edible essence of 0.30%, wherein said sweeting agent be sucralose,
Aspartame or its mixture.
In certain embodiments, oseltamivir phosphate buccal tablet of the present invention, comprise the oseltamivir phosphate of 8.0%～40.0%, 48.0～85.0%
Filler, the disintegrating agent of 2.0%～5.0%, the binding agent of 0.5%～3.0%, the sweeting agent of 0.5%～2.0%, the lubricant of 0.5%～1.0%,
The fluidizer of 0.2%～0.5%, the pH adjusting agent of 0.5%～2.0% and 0.1%～the edible essence of 0.3%, wherein said sweeting agent be sucralose or
Aspartame.
In certain embodiments, oseltamivir phosphate buccal tablet of the present invention, comprise the oseltamivir phosphate of 8.0%～40.0%, 48.0～85.0%
Filler, the disintegrating agent of 2.0%～5.0%, the binding agent of 0.5%～3.0%, the sweeting agent of 0.5%～2.0%, the lubricant of 0.5%～1.0%,
The fluidizer of 0.2%～0.5%, the pH adjusting agent of 0.5%～2.0% and 0.1%～the edible essence of 0.3%, wherein said sweeting agent be sucralose,
Aspartame or its mixture.
On the other hand, present invention also offers a kind of method preparing described oseltamivir phosphate oral cavity disintegration tablet, said method comprising the steps of:
A) oseltamivir phosphate, filler, the first disintegrating agent and binding agent are joined premixing in granulation pot uniform；
B) use peristaltic pump to add purified water to pelletize；
C) being dried in fluid bed, then sieve granulate, it is thus achieved that is dried granule；
D) in the dry granule obtained, sweeting agent, lubricant, the second disintegrating agent and fluidizer, mix homogeneously and tabletting are then added.
In certain embodiments, d) step can also add edible essence.
On the other hand, present invention also offers a kind of method preparing described oseltamivir phosphate chewable tablet, said method comprising the steps of:
A) oseltamivir phosphate, filler, disintegrating agent and binding agent are joined premixing in granulation pot uniform；
B) use peristaltic pump to add purified water to pelletize；
C) being dried in fluid bed, then sieve granulate, it is thus achieved that is dried granule；
D) in the dry granule obtained, sweeting agent, lubricant, disintegrating agent and fluidizer, mix homogeneously and tabletting are then added.
In certain embodiments, in a) step, pH adjusting agent can also be joined premixing in granulation pot uniform.
In certain embodiments, d) step can also add edible essence.
In certain embodiments, use the punch die tabletting of special shape, the sheet heart of chewable tablet in d) step, leave 3mm3～120mm3Hole,
Unique, reduce child simultaneously and gulp down the risk of suffocating brought by mistake.
On the other hand, present invention also offers a kind of method preparing described oseltamivir phosphate buccal tablet, said method comprising the steps of:
A) oseltamivir phosphate, filler, disintegrating agent and binding agent are joined premixing in granulation pot uniform；
B) use peristaltic pump to add purified water to pelletize, described purified water has been dissolved part sweeting agent；
C) being dried in fluid bed, then sieve granulate, it is thus achieved that is dried granule；
D) in the dry granule obtained, remainder sweeting agent, lubricant, disintegrating agent and fluidizer, mix homogeneously and tabletting are then added.
In certain embodiments, in a) step, pH adjusting agent can also be joined premixing in granulation pot uniform.
In certain embodiments, d) step can also add edible essence.
In b) step, dissolving part sweeting agent is in purified water, uses the wet mode added add and pelletize, adds the uniformity of sweeting agent, keep away
Exempt from during buccal tablet buccal because uneven sweet taste brings the dislike of patient.
In certain embodiments, use the punch die tabletting of special shape, the sheet heart of buccal tablet in d) step, leave 3mm3～120mm3Hole,
Unique, reduce child simultaneously and gulp down the risk of suffocating brought by mistake.
Detailed description of the invention
In order to make those skilled in the art be more fully understood that technical scheme, disclose some non-limiting embodiments further below to the present invention
It is described in further detail.
Reagent used in the present invention all can be buied from the market or can be prepared by method described in the invention.
The different sweeting agent of embodiment 1 is on oseltamivir phosphate oral cavity disintegration tablet stability and the impact of mouthfeel
Preparation prescription
Preparation method:
Recipe quantity is separately added into oseltamivir phosphate, mannitol, sorbitol, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and polyvidone and adds system
In grain pot, premix is uniformly, granulator blade rotating speed 150rpm, cutter rotating speed 1500rpm.Peristaltic pump is used to add pre-composition 17%～23% weight
Purified water pelletize, peristaltic pump rotating speed 100rpm, shower nozzle aperture 1.0mm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cut
Cutter rotating speed 3000rpm.Use fluid bed drying, inlet temperature 55 DEG C；Being dried granule uses comil pelletizing machine to cross 045R screen cloth granulate.?
It is dried in granule, adds sucralose or saccharin sodium or aspartame or acesulfame potassium or steviosin, Pulvis Talci, sodium stearyl fumarate, the poly-dimension of crosslinking
Ketone, peach flavor, orange flavor or cream flavour, mix homogeneously.Use Fitow tabletting machine.Use double aluminum packaging again, obtain oral cavity disintegration tablet and produce
Product.
Above-mentioned gained oseltamivir phosphate oral cavity disintegration tablet is carried out mouthfeel investigation, investigates method and result is as follows:
Recruit 20 volunteers, oral a piece of oral cavity disintegration tablet, do not chew, suck 30 seconds, then spue, single experiment is more than or equal to 1 interval time
My god；Then the problem in allowing volunteer answer a questionnaire, is estimated key issue.
Above-mentioned gained oseltamivir phosphate oral cavity disintegration tablet is carried out study on the stability, investigates result and method is as follows:
Detection method:
Chromatographic column: Waters Xbridge C8,5 μm, 4.6mm × 250mm
Detection wavelength: 207nm
Column temperature: 50 DEG C
Flow velocity: 1.2mL/min
Sample size: 20 μ L
The operation time: about 35min
Rear operation: 3min.
Gradient:
Mobile phase A: weigh potassium dihydrogen phosphate 6.80g, is dissolved in 1L ultra-pure water, mixing, regulates pH to 6.0 with potassium hydroxide, uses 0.45 μm
Water system membrane filtration, ultrasonic and get final product.
Mobile phase B: methanol
Flowing phase C: acetonitrile
With reference to 2010 editions second annex Ⅹ Ⅸ crude drug of Chinese Pharmacopoeia with pharmaceutical preparation stability test guideline to prescription 1～5 phosphorus described above
Acid Oseltamivir oral cavity disintegration tablet is accelerated experiment investigation.Inspecting by random samples behind 0 day, the 3rd month and 6th month, detection has related substance project；
Detection of Stability result is as follows:
Above-mentioned 5 prescriptions, are screened sweeting agent and correctives, the evaluation suited one's taste by volunteer respectively, acesulfame potassium and steviosin two kinds
Sweeting agent is poor to the effectiveness comparison of taste masking, and taste is the most bitter, it is difficult to accept；The taste masking effect of saccharin sodium is general, and volunteer evaluates the most not very willing taking；
The taste masking effect of aspartame and sucralose is preferable, and part volunteer is ready to take, and part volunteer can also accept when not having other medicines to take,
Comprehensive grading, the taste masking effect of sucralose is best, and volunteer's acceptable degree is the highest.
In terms of study on the stability, above-mentioned 5 prescriptions, under acceleration environment, acesulfame potassium and two kinds of sweeting agents of steviosin cause impurity to be significantly increased；Saccharin
Sodium impurity stability is the best, but has a unknown impuritie to exceed 0.20% when accelerating June；Aspartame and stability of trichlorosucrose are preferable, add
Speed is after 6 months, and impurity is more stable.
Peach flavor that prescription 1 and prescription 3 are respectively adopted, orange flavor, impurity has good stability；It is special that oseltamivir phosphate crude drug has
Abnormal smells from the patient, uses both essence all can preferably cover the bad smell of crude drug, and volunteer evaluates abnormal smells from the patient deflection smelling good.
As can be seen here, sweeting agent is sucralose or aspartame, when essence is peach flavor or orange flavor (such as prescription 1 or 3), and phosphoric acid
Oseltamivir oral cavity disintegration tablet mouthfeel and stability are the most optimal.
Embodiment 2 oseltamivir phosphate oral cavity disintegration tablet different size formulation study
Preparation prescription
Preparation method is with reference to the preparation method of embodiment 1
Above-mentioned gained oseltamivir phosphate oral cavity disintegration tablet is carried out mouthfeel investigation, investigates result and method is as follows:
Recruit 20 volunteers, oral a piece of oral cavity disintegration tablet, do not chew, suck 30 seconds, then spue, single experiment is more than or equal to 1 interval time
My god；Then the problem in allowing volunteer answer a questionnaire；Key issue is estimated.
Disintegration time and friability is carried out to obtaining oseltamivir phosphate oral cavity disintegration tablet prepared by the prescription 1 and 6-9 described in embodiment 2.
Disintegration time and friability testing conditions: disintegration, according to Chinese Pharmacopoeia 2010 editions, the detection disintegrate of annex X A disintegration of tablet method, collapses
Solution medium is water, and water temperature controls at 37 ± 1 DEG C.
Friability detects according to Chinese Pharmacopoeia 2010 editions, annex X G tablet friability inspection technique.
Disintegration time and friability testing result are as follows:
Prescription 1,7,9 carries out taste appraisal, and suit one's taste has a certain impact different size (different API ratio).API prescription ratio exists
Time 2.63% (5mg specification), the overall evaluation is best, increases with API ratio, and when 39.4% (75mg specification), the overall evaluation slightly reduces, but all can
In the range of accepting, in the case of sick, major part volunteer is ready to select this dosage form.
Oseltamivir phosphate oral cavity disintegration tablet is prepared, through investigating disintegration time and friability, phosphoric acid according to the prescription 1 in embodiment 2 and prescription 6～9
Oseltamivir ratio in orally disintegrating tablet prescription has good disintegrate effect in the range of 2.6%～40.0%.
Embodiment 3 oseltamivir phosphate chewable tablet
Preparation prescription
Preparation method:
Recipe quantity is separately added into oseltamivir phosphate, mannitol, microcrystalline Cellulose, monohydrate potassium, cross-linking sodium carboxymethyl cellulose and polyvidone
Add premix in granulation pot uniform, granulator blade rotating speed 150rpm, cutter rotating speed 1500rpm.Peristaltic pump is used to add pre-composition 17%～23%
The purified water of weight is pelletized, peristaltic pump rotating speed 100rpm, shower nozzle aperture 1.0mm, liquid feeding and pelletization granulator blade rotating speed 150rpm,
Cutter rotating speed 3000rpm；Use fluid bed drying, inlet temperature 55 DEG C；Being dried granule uses comil pelletizing machine to cross 045R screen cloth granulate.
In dry granule, add sucralose, silica sol, sodium stearyl fumarate, peach flavor, mix homogeneously.Use Fitow tabletting
Machine tabletting, then use double aluminum packaging, obtain chewable tablet product.
Above-mentioned gained oseltamivir phosphate chewable tablet is carried out mouthfeel investigation, investigates method and result is as follows:
Recruit 10 volunteers, an oral tablet recipe 10 or the chewable tablet of prescription 11, chew 30 seconds, then spue, single experiment is more than interval time
Equal to 1 day.Then the problem in allowing volunteer answer a questionnaire, is estimated key issue:
Obtain oseltamivir phosphate chewable tablet prepared to the prescription 10～15 described in embodiment 3 carries out disintegration time and friability.
Disintegration time and friability testing conditions: disintegration, according to Chinese Pharmacopoeia 2010 editions, the detection disintegrate of annex X A disintegration of tablet method, collapses
Solution medium is water, and water temperature controls at 37 ± 1 DEG C.
Friability detects according to Chinese Pharmacopoeia 2010 editions, annex X G tablet friability inspection technique.
Disintegration time and friability testing result are as follows:
The oseltamivir phosphate chewable tablet prepared according to prescription 10 in embodiment 3 and prescription 11, investigates through mouthfeel contrast, investigates result and shows
Solid circles sheet not there are differences in mouthfeel with hollow Special-shaped sheet, good mouthfeel, easily accepts for experimenter.
Oseltamivir phosphate chewable tablet is prepared, through investigating disintegration time and friability, phosphoric acid Ao Sita according to the prescription 10～15 in embodiment 3
Wei ratio in chewable tablet prescription has good disintegrate effect in the range of 1.32%～39.4%.
Embodiment 4 oseltamivir phosphate buccal tablet
Preparation prescription
Preparation method:
Recipe quantity is separately added in oseltamivir phosphate, mannitol, cross-linking sodium carboxymethyl cellulose, polyvidone, monohydrate potassium addition granulation pot
Premix is uniform, granulator blade rotating speed 150rpm, cutter rotating speed 1500rpm.The sucralose of prescription ratio is dissolved in and accounts for pre-composition 17%～23%
Water in, obtain granulation liquid, use peristaltic pump to add granulation liquid and pelletize, peristaltic pump rotating speed 100rpm, shower nozzle aperture 1.0mm, liquid feeding and system
Grain process granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm；Use fluid bed drying, inlet temperature 55 DEG C；It is dried granule to use
Comil pelletizing machine crosses 045R screen cloth granulate.In dry granule, add sucralose, silica sol, sodium stearyl fumarate, honey peach
Essence, mix homogeneously.Use Fitow tabletting machine, then use double aluminum packaging, obtain buccal tablet product.
Above-mentioned gained oseltamivir phosphate buccal tablet is carried out mouthfeel investigation, investigates method and result is as follows:
Recruit 10 volunteers, the buccal tablet of an oral tablet recipe 16～17, until buccal tablet is completely dissolved, then spue, when single experiment is spaced
Between more than or equal to 1 day.Then the problem in allowing volunteer answer a questionnaire, is estimated key issue:
Obtain oseltamivir phosphate buccal tablet prepared to the prescription 16～17 described in embodiment 4 carries out mouthfeel evaluation.Crude drug is accounting example in prescription
Reducing, overall mouthfeel averagely improves；By the alteration of form of buccal tablet, by original solid circles sheet, changing abnormity hollow sheet into, this is felt by volunteer
Relatively new to outward appearance, beneficially child patient is taken medicine, and is hollow design, it is to avoid child gulps down the risk of suffocating brought by mistake in the middle of buccal tablet.
Embodiment 5 oseltamivir phosphate buccal tablet
Preparation prescription
Preparation method:
Recipe quantity is separately added in oseltamivir phosphate, mannitol, cross-linking sodium carboxymethyl cellulose, polyvidone, monohydrate potassium addition granulation pot
Premix is uniform, granulator blade rotating speed 150rpm, cutter rotating speed 1500rpm.By the sucralose of prescription ratio or/and aspartame is dissolved in accounts for
In the water of pre-composition 17%～23%, obtain granulation liquid, use peristaltic pump to add granulation liquid and pelletize, peristaltic pump rotating speed 100rpm, shower nozzle aperture
1.0mm, liquid feeding and pelletization granulator blade rotating speed 150rpm, cutter rotating speed 3000rpm；Use fluid bed drying, inlet temperature 55 DEG C；
Being dried granule uses comil pelletizing machine to cross 045R screen cloth granulate.In dry granule, addition sucralose/aspartame, silica sol,
Sodium stearyl fumarate, peach flavor, mix homogeneously.Use Fitow tabletting machine, then use double aluminum packaging, obtain buccal tablet product.
Above-mentioned gained oseltamivir phosphate buccal tablet is carried out mouthfeel investigation, investigates method and result is as follows:
Recruit 10 volunteers, the buccal tablet of an oral tablet recipe 16,20～23, until buccal tablet is completely dissolved, then spue, between single experiment
Interval is more than or equal to 1 day.Then the problem in allowing volunteer answer a questionnaire, is estimated key issue:
Carry out mouthfeel evaluation to obtaining oseltamivir phosphate buccal tablet prepared by the prescription 20-23 described in embodiment 5, when sweeting agent ratio is less, cover
Taste effect is general, sucralose is dissolved in the taste masking effect that water wet granulation brings preferable, uses sucralose and two sweeting agents combinations of aspartame
Also there is good taste masking effect.
To sum up described in embodiment,
From above example 1～5, use oseltamivir phosphate, sucralose or/and prepared by aspartame and other pharmaceutically acceptable adjuvants
Oral cavity disintegration tablet, chewable tablet or buccal tablet, there is good mouthfeel；Enable to oseltamivir phosphate preparation simultaneously and there is good stability, it is ensured that
The drug safety of medicine.
The method of the present invention is described by preferred embodiment, and related personnel substantially can be to herein in present invention, spirit and scope
Described methods and applications are modified or suitably change and combine, and realize and apply the technology of the present invention.Those skilled in the art can use for reference herein
Content, is suitably modified technological parameter and realizes.Special needs to be pointed out is, all similar replacements and change be for a person skilled in the art aobvious and
Being clear to, they are considered as being included in the present invention.
Claims (24)
1. an oseltamivir phosphate tablet, comprises oseltamivir phosphate, sweeting agent and other pharmaceutically acceptable adjuvants, and wherein said sweeting agent is
Sucralose or aspartame.
2. an oseltamivir phosphate tablet, comprises oseltamivir phosphate, sweeting agent and other pharmaceutically acceptable adjuvants, and wherein said sweeting agent is
Sucralose, aspartame or its mixture.
Tablet the most according to claim 1, the content of wherein said sweeting agent is 0.1%～5.0%.
Tablet the most according to claim 3, wherein said pharmaceutically acceptable adjuvant is filler, binding agent, disintegrating agent, fluidizer, profit
One or more in lubrication prescription, pH adjusting agent and edible essence.
Tablet the most according to claim 4, wherein said tablet is oral cavity disintegration tablet, comprises 2.0%～50.0% or 2.5～40.0% or 15.0%～40.0%
Oseltamivir phosphate.
Tablet the most according to claim 5, comprises the oseltamivir phosphate of 2.5%～40.0%, 45.0～the filler of 90.0%, 4.0%～10.0%
Disintegrating agent, the binding agent of 0.5%～3.0%, the sweeting agent of 0.2%～2.0%, the lubricant of 0.5%～1.0%, the fluidizer of 0.2%～1.0%, and
The edible essence of 0.05%～0.3%, wherein said disintegrating agent comprises the first disintegrating agent and the second disintegrating agent.
Tablet the most according to claim 4, wherein said tablet is chewable tablet, comprises 1.0%～50.0% or 2.5～40.0% or 5.0%～20.0%
Oseltamivir phosphate.
Tablet the most according to claim 7, comprises the oseltamivir phosphate of 1.3%～40.0%, 48.0～the filler of 94.0%, 1.0%～5.0%
Disintegrating agent, the binding agent of 1.0%～3.0%, the sweeting agent of 0.2%～2.0%, the lubricant of 0.5%～1.0%, the fluidizer of 0.2%～0.5%,
The pH adjusting agent of 0.25%～2.0% and the edible essence of 0.1%～0.30%.
Tablet the most according to claim 8, the sheet heart of described tablet, use special punch die or other modes to make the sheet heart have a hole running through two sides
Hole.
Tablet the most according to claim 4, wherein said tablet is buccal tablet, and it comprises 2.0%～the department of phosphoric acid Austria of 50.0% or 8.0%～40.0%
His Wei.
11. tablets according to claim 10, comprise the oseltamivir phosphate of 8.0%～40.0%, 48.0～the filler of 85.0%, 2.0%～5.0%
Disintegrating agent, the binding agent of 0.5%～3.0%, the sweeting agent of 0.5%～2.0%, the lubricant of 0.5%～1.0%, the fluidizer of 0.2%～0.5%,
The pH adjusting agent of 0.5%～2.0% and the edible essence of 0.1%～0.3%.
12. tablets according to claim 11, the sheet heart of described tablet, use special punch die or other modes to make the sheet heart have a hole running through two sides
Hole.
13. according to the arbitrary described tablet of claim 1～12, the content of wherein said oseltamivir phosphate be 5mg, 10mg, 30mg, 45mg or
75mg。
14. according to the arbitrary described tablet of claim 4～12, and wherein said filler is lactose, microcrystalline Cellulose, mannitol, sorbitol, Fructus Hordei Germinatus
One or more in sugar alcohol, xylitol, corn starch, dextrin, maltodextrin, pregelatinized Starch, sucrose and gelatin.
15. according to the arbitrary described tablet of claim 4～12, and wherein said binding agent is methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl fibre
One or more in dimension element, polyvidone, microcrystalline Cellulose and low-substituted hydroxypropyl cellulose.
16. according to the arbitrary described tablet of claim 4～12, and wherein said disintegrating agent is cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl
One or more in Starch Sodium, corn starch, low-substituted hydroxypropyl cellulose.
17. according to the arbitrary described tablet of claim 4～12, and wherein said fluidizer is silica sol or Pulvis Talci or its mixture.
18. according to the arbitrary described tablet of claim 4～12, and wherein said lubricant is sodium stearyl fumarate, magnesium stearate, calcium stearate, hard
One or many in fat acid zinc, sucrose stearate, hydrogenated vegetable oil, stearic acid, silica sol, Pulvis Talci and polyethylene glycol 6000
Kind.
19. according to the arbitrary described tablet of claim 4～12, and wherein said pH adjusting agent is citric acid and hydrate salt pharmaceutically acceptable with it thereof
Mixture, dihydrogen citrate alkali metal salt, sodium lactate or sodium succinate.
20. according to the arbitrary described tablet of claim 4～12, and wherein said edible essence is peach flavor, orange flavor, strawberry essence, butter
One or more in essence, apple essence, flavoring pineapple essence and flavoring banana essence.
The method of 21. 1 kinds of tablets prepared described in claim 6, comprises the following steps:
A) oseltamivir phosphate, filler, the first disintegrating agent and binding agent are joined premixing in granulation pot uniform；
B) use peristaltic pump to add purified water to pelletize；
C) being dried in fluid bed, then sieve granulate, it is thus achieved that is dried granule；
D) then adding sweeting agent, lubricant, the second disintegrating agent, fluidizer and edible essence in the dry granule obtained, mix homogeneously is also
Tabletting；
Wherein said sweeting agent is sucralose or aspartame.
The method of 22. 1 kinds of tablets prepared described in claim 8, comprises the following steps:
A) oseltamivir phosphate, filler, disintegrating agent and binding agent are joined premixing in granulation pot uniform；
B) use peristaltic pump to add purified water to pelletize；
C) being dried in fluid bed, then sieve granulate, it is thus achieved that is dried granule；
D) then in obtaining dry granule, sweeting agent, lubricant, fluidizer and edible essence, mix homogeneously tabletting are added；
Wherein said sweeting agent is sucralose or aspartame.
The method of 23. 1 kinds of tablets prepared described in claim 11, comprises the following steps:
A) oseltamivir phosphate, filler, disintegrating agent and binding agent are joined premixing in granulation pot uniform；
B) use peristaltic pump to add purified water to pelletize, described purified water has been dissolved part sweeting agent；
C) being dried in fluid bed, then sieve granulate, it is thus achieved that is dried granule；
D) then in obtaining dry granule, remainder sweeting agent, lubricant and fluidizer, mix homogeneously tabletting are added；
Wherein said sweeting agent is sucralose or aspartame.
24. according to the method described in claim 22 or 23, in wherein said a) step, also includes joining pH adjusting agent premix in granulation pot
Close uniformly.
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| CN113116827A (en) * | 2019-12-30 | 2021-07-16 | 上海复星星泰医药科技有限公司 | Oseltamivir phosphate granules and preparation method thereof |
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| CN115531335B (en) * | 2022-11-02 | 2024-01-30 | 合肥医工医药股份有限公司 | Oselta phosphate Wei Kou disintegrating tablet and preparation method thereof |
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